The SCOR proposes an integrated set of basic and clinical studies aiming to define molecular mechanisms of atherogenesis at the level of the arterial wall. Effects on atherogenesis of arterial wall enzymes, lipoproteins and proteoglycans will be investigated in transgenic mouse models and in cell culture. A parallel set of investigations in humans will determine the relevance of mechanisms defined in mice and in cell culture to the pathophysiology of human atherosclerosis. Thus, the SCOR will define new mechanisms of atherogenesis and evaluate their significance in humans. Project 6 (Tall) will evaluate the mechanisms of atheroma foam cell regression that result from the interaction of HDL or its apolipoproteins with macrophage ABCA1. Project 1 (Tabas) will investigate the role of arterial wall sphingomyelinase in lipoprotein retention and aggregation, and macrophage foam cell formation. Project 7 (Williams) will evaluate the role of arterial wall proteoglycans in lipoprotein retention, and will study the mechanisms and significance of the recent finding that mice deficient in decorin proteoglycan have acclerated atherogenesis. Project 8 (Goldberg) will study the role of perlecan in atherogenesis, and will determine the role of this proteoglycan in preventing penetration of atherogenic lipoproteins into the arterial wall. The four cores will be A) Administrative; B) Clinical/Biostatistics; Q Gene Expression Profiling; and D) Pathology. The major theme of the SCOR is to investigate the interactions of plasma lipoproteins with proteoglycans, enzymes and cells of the arterial wall, and to define molecular mechanisms that promote or ameliorate atheroma foam cell formation. The studies are likely to reveal novel information about the role of specific arterial wall molecules in atherosclerosis in mice and humans, leading to improved diagnosis and treatment of this disease.